Genotype‐based association test for general pedigrees: The genotype‐PDT

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Abstract
Many family‐based tests of linkage disequilibrium (LD) are based on counts of alleles rather than genotypes. However, allele‐based tests may not detect interactions among alleles at a single locus that are apparent when examining associations with genotypes. Family‐based tests of LD based on genotypes have been developed, but they are typically valid as tests of association only in families with a single affected individual. To take advantage of families with multiple affected individuals, we propose the genotype‐pedigree disequilibrium test (geno‐PDT) to test for LD between marker locus genotypes and disease. Unlike previous tests for genotypic association, the geno‐PDT is valid in general pedigrees. Simulations to compare the power of the allele‐based PDT and geno‐PDT reveal that under an additive model, the allele‐based PDT is more powerful, but that the geno‐PDT can have greater power when the genetic model is recessive or dominant. Perhaps the most important property of the geno‐PDT is the ability to test for association with particular genotypes, which can reveal underlying patterns of association at the genotypic level. These genotype‐specific tests can be used to suggest possible underlying genetic models that are consistent with the pattern of genotypic association. This is illustrated through an application to a candidate gene analysis of the MLLT3 gene in families with Alzheimer disease. The geno‐PDT approach for testing genotypes in general family data provides a useful tool for identifying genes in complex disease, and partitioning individual genotype contributions will help to dissect the influence of genotype on risk. Genet Epidemiol 25:203–213, 2003.

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